EP3099330A1 - Solution alcoolique d'alprostadil stable - Google Patents

Solution alcoolique d'alprostadil stable

Info

Publication number
EP3099330A1
EP3099330A1 EP15709819.5A EP15709819A EP3099330A1 EP 3099330 A1 EP3099330 A1 EP 3099330A1 EP 15709819 A EP15709819 A EP 15709819A EP 3099330 A1 EP3099330 A1 EP 3099330A1
Authority
EP
European Patent Office
Prior art keywords
acid
composition according
concentration
alprostadil
equal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP15709819.5A
Other languages
German (de)
English (en)
Other versions
EP3099330B1 (fr
Inventor
Franz HÄUSLER
Helmut Scheidl
Daniel Wagner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gebro Holding GmbH
Original Assignee
Gebro Holding GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gebro Holding GmbH filed Critical Gebro Holding GmbH
Priority to EP18150928.2A priority Critical patent/EP3395367A1/fr
Publication of EP3099330A1 publication Critical patent/EP3099330A1/fr
Application granted granted Critical
Publication of EP3099330B1 publication Critical patent/EP3099330B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
    • H01M10/00—Secondary cells; Manufacture thereof
    • H01M10/42—Methods or arrangements for servicing or maintenance of secondary cells or secondary half-cells
    • H01M10/425—Structural combination with electronic components, e.g. electronic circuits integrated to the outside of the casing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
    • Y02E60/10—Energy storage using batteries

Definitions

  • Stable alcoholic solution of Alprostadil Alprostadil is a substance described in the European Pharmacopoeia from the group of prostaglandin analogues. It is identical to the body's own prostaglandin E1. Its main physiological effects are vasodilation and inhibition of platelet aggregation. From this profile of action, the most important indications are the treatment of erectile dysfunction, the treatment of peripheral arterial disease and the short-term treatment of certain neonatal heart defects. As pharmaceutical dosage forms are mainly parenteral, for the treatment of erectile dysfunction and topical dosage forms available. Alprostadil is a chemically extremely unstable drug.
  • the commentary of the European Pharmacopoeia called the elimination of water to prostaglandin Ai (PGA1) as the most important degradation reaction.
  • This degradation product is referred to in the monograph of the European Pharmacopoeia as impurity A. It may further react in an isomerization reaction to prostaglandin Bi, which is referred to as Contamination B in the European Pharmacopoeia monograph.
  • Contamination B in the European Pharmacopoeia monograph.
  • the European Pharmacopoeia names eleven impurities with their respective molecular structure.
  • the initial reaction of the degradation namely the elimination of water to PGA1 takes place particularly easily under acidic or basic conditions, with divalent and trivalent cations additionally impairing the stability in ethanolic solution.
  • the stabilizing adjuvant used is mainly alpha-cyclodextrin (Alfadex).
  • Commercial names of such products include Caverject® (Pfizer, Pharmacia), Prostavasin® (UCB Pharma) or Viridal® (UCB Pharma).
  • CN 102688203 describes a lyophilizate containing alprostadil in which a mixture of dextran and hydroxypropyl-beta-cyclodextrin is used for stabilization.
  • Oily and liposomal preparations and concentrates are also described in the literature. The latter are used in Japan e.g. also marketed under the brand names Liple® (Tanabe) and Palux® (Taisho).
  • Topical formulations are pure lipogels which include natural oils, fatty acids, fatty alcohols or synthetic lipids, e.g. Isopropyl myristate, and in addition with thickening agents, e.g. Poloxamers, can be thickened. Described are such lipogel e.g. in KR 2001001 1625 and JP 0383925.
  • the solution of the active ingredient in absolute ethanol represents the closest prior art.
  • the main advantage of the ethanolic solution is that they are more easily processed into a solution ready for infusion Can be used as a lyophilisate.
  • the lyophilisate must first be reconstituted in a first step in the vial with a suitable solvent; then this solution must be in a second Step of the infusion solution can be added.
  • the ampoule can be added directly in one step to an infusion solution. This simplification of handling also reduces the risk of manipulation errors and the risk of introducing germs.
  • Another advantage of the ethanolic solution is the very simple composition of the formulation consisting solely of the active ingredient and the solvent. It allows a much simpler and cheaper compared to a lyophilizate production.
  • Another advantage is that the simple composition of the formulation substantially facilitates the analysis of the preparation. Due to the low dosage of the active ingredient, quality controls must be used to quantify impurities down to a concentration range of 10 ng / ml. At such low concentrations, it is a great advantage if the preparation is directly analyzable without processing and without separation of excipients.
  • the object of the invention is therefore to develop such a formulation which, in addition to the previous advantages of the ethanolic solution (eg Pridax®) contains a lower concentration of degradation products, has improved stability and longer shelf life and a less severe cooling regime in the Manufacture, during transport and storage required.
  • This object is achieved in that the solution of alprostadil contains a small amount of an acidic component.
  • the invention thus provides a liquid pharmaceutical composition, in particular as a concentrate for the further preparation of an infusion solution containing alprostadil as active ingredient dissolved in at least one non-aqueous solvent containing at least one acid or acting as an acid or proton donating substance as a stabilizer for the active ingredient.
  • the solution according to the invention in comparison to the prior art (Pridax® 20 ⁇ g / ml concentrate for the preparation of an infusion solution), has a substantially better storage stability, in particular that the formation of the main degradation product PGA1 is markedly slowed down.
  • This stabilizing effect is so pronounced that the preparation according to the invention is suitable for achieving all the objectives of the invention.
  • the upper specification limit for the degradation product PGA1 can be reduced (e.g., from 6% to 4%).
  • the shelf life of the product is prolonged (e.g., from 18 months to 36 months).
  • the service life of the solution during the preparation at room temperature is increased (for example, from 4 to 8 hours), whereby the batch size can be increased.
  • the analytical method for the preparation is not complicated by the addition of the acidic component.
  • inorganic acids are amounts which lead to an acid concentration of 500 ⁇ g / ml or less.
  • the concentration of the active ingredient in ethanolic alprostadil solutions in the unit ⁇ g / ml is given.
  • the concentration of the acid in the unit ⁇ g / ml is also indicated in this invention.
  • a conversion to the unit ⁇ g / g can be made at any time by dividing by the density of the solvent (absolute alcohol about 0.789 g / ml).
  • the amount of acid results in the unit ⁇ , corresponding to ⁇ / ⁇ .
  • this concentration can also be converted at any time into the unit ⁇ g / ml.
  • low acid concentrations of 0.05-500 ⁇ g / ml are used, preferably 0.1-100 ⁇ g / ml, in particular 5-50 ⁇ g / ml.
  • an acid addition of likewise 20 ⁇ g / ml is provided for stabilizing an ethanolic solution containing 20 ⁇ g / ml alprostadil.
  • this advantageous effect occurs when alprostadil is present in a concentration of 1-1000 ⁇ g / ml, preferably 5-750 ⁇ g / ml, in particular 20-500 ⁇ g / ml.
  • the terms "acid component” and “acid” mean compounds according to the acid definition of Brönsted and Lowry, ie substances which are capable of giving off protons or of acting as proton donors.
  • an acid To act as a proton donor relative to the alprostadil, an acid must have a pks value lower than 4.85, the pks value of the alprostadil. It This can be both inorganic and organic substances.
  • the acids can be both monobasic and polybasic.
  • compositions according to the invention are those organic and inorganic acids which can be used in parenteral drugs because of their toxicological profile and which dissolve completely and clearly in the concentrations according to the invention in the solvents used, in particular in absolute alcohol, even at low temperatures .
  • examples of such acids are hydrochloric acid, acetic acid, citric acid, malic acid, lactic acid, tartaric acid or acetylcysteine.
  • organic carboxylic acids especially because of their broad stabilization optimum polybasic, organic hydroxycarboxylic proved.
  • acids such as e.g. Citric acid, malic acid or tartaric acid used, particularly preferred is the use of DL-malic acid.
  • inorganic acids in particular those selected from the group of hydrochloric acid or phosphoric acid.
  • Stability tests have shown that an improvement in stability can be achieved essentially with all those acids which fulfill the conditions specified here. Stabilization can always be recognized both from the fact that the content of alprostadil decreases more slowly during a test storage, and from the fact that the content of impurities, in particular of impurity A, increases more slowly.
  • concentration at which maximum stability enhancement occurs, as well as the extent of stability improvement, are significantly dependent on the type of acid used, especially on its pKsI value, with the stabilizing effect going through an optimum of concentration in all cases.
  • Table 1 thus contains advantageous concentrations of acids which can be used advantageously, in which experimentally the best stabilizations for alprostadil have been found.
  • the inorganic or organic acid has a pKsI value of greater than or equal to 2 to less than 4.8 and in a concentration of 0.5 to 500 ⁇ g / ml, in particular from 1 to 250 ⁇ g / ml.
  • non-aqueous solvent is understood herein to mean solvents which do not predominantly consist of water or hardly contain water. However, small quantities or residual amounts of water up to a few% by weight may be present. Accordingly, the nonaqueous solvent advantageously has a maximum water content of up to 7.4% by weight, in particular up to 4% by weight, preferably up to 0.1% by weight. Experimentally could be determined by these amounts of water no disturbing deterioration of stability.
  • non-aqueous solvent propylene glycol, 1,3-butanediol, ethyl acetate, ethanol 96% PhEur (95.1-96.9% (v / v) corresponding to 92.6-95.2% by weight) or anhydrous ethanol PhEur (min. 99.5% (v / v) corresponding to at least 99.2% by weight) or absolute ethanol, respectively, according to the definitions and requirements of the European Pharmacopoeia.
  • Anhydrous ethanol PhEur (at least 99.5% (v / v)) and absolute ethanol are understood as synonyms, often referred to as 100% ethanol, which in the present case is also synonymous.
  • solvents are applicable in parenteral formulations due to their toxicological profile and the active ingredient alprostadil is soluble therein in sufficient concentration. Mixtures of these solvents can be used advantageously.
  • the solvent may also be added to solubilizers such as polyethylene glycol or polysorbate.
  • composition is present when the composition is finally and exclusively from alprostadil as the active ingredient dissolved in at least one non-aqueous solvent, and from at least one acid or acting as an acid or proton donating substance as a stabilizer for the active substance and does not contain any other ingredients, excipients or additives.
  • the term primary packaging means packaging means which are in direct contact with the drug. On the one hand, they must comply with the requirements of the relevant pharmacopoeias and, moreover, they must be selected in such a way that they minimize as little as possible substances which are detrimental to the stability of the contents, e.g. basic impurities.
  • Suitable materials from which usable for sensitive parenterals primary packaging means are known in the art. Conceivable, for example, but not limited to tubular glass or glass of hydrolytic class I or hydrolytic class II, with internal coating. Also applicable, for example, but not exclusively plastics such as COP, COC, PP, PE, HDPE, Teflon, PA.
  • Preferred primary containers are glass ampoules or vials consisting of tubular glass of hydrolytic class I.
  • the primary sealing material for Vials come stopper from bromobutyl rubber or chlorobutyl rubber, preferably coated, in question.
  • Other possible primary containers include, but are not limited to, carpules or prefilled syringes. It follows that a good stabilization of the composition or alprostadil in a kit-of-parts combination of the inventive composition filled or contained in a glass ampoule, glass vial, carpule or pre-filled syringe, is present.
  • the acid is preferably added to the solvent during the preparation process of the finished medicinal product. Possible embodiments would be to add the acid during the production process of the solvent or another excipient or during the production process of the active ingredient alprostadil.
  • the pharmaceutical composition according to the invention is advantageously a concentrate for the preparation of a parenterally administered infusion solution, which concentrate can be prepared or prepared, in particular by a dilution step, to the ready-to-use infusion solution for parenteral administration.
  • a dilution e.g. with isotonic, aqueous solution, preferably with physiological saline, in particular in a ratio of 1: 10 to 1: 500, preferably 1: 20 to 1: 250, then the ready-to-use parenteral solution for infusion is available.
  • composition is possible as a concentrated injection solution for direct administration.
  • a method for producing a liquid pharmaceutical composition is accordingly provided, in the course of which the active substance alprostadil dissolved in a non-aqueous solvent as described above, at least one acid or one as acid or Proton donor acting substance, as described above, is added as a stabilizer for the active ingredient.
  • the invention furthermore relates to the use of at least one acid or a substance acting as an acid or proton donor, as described above, as a stabilizer for the active substance alprostadil or for a liquid pharmaceutical as described above Composition containing the active ingredient alprostadil dissolved in a non-aqueous solvent.
  • composition of the invention is used in its most important indication for the treatment of chronic arterial disease in stages III and IV, when a therapy to dilate the blood vessels is not possible or unsuccessful.
  • Example 4 represents a particularly preferred embodiment of the invention.
  • Table 3 Formulation examples for preparations in alprostadil concentrations 10-1000 ⁇ g / ml
  • PGE 1 10 10 500 500 500 1000 1000 500 500
  • the content of PGE1 is measured in the unit ⁇ g / ml). In all subsequent results tables, the content is given in% of the starting value of PGE1 for better comparability.
  • the concentration of the degradation product PGA1 is measured and expressed in percent by mass (% m / m) based on the declared content of PGE1.
  • the absolute values of PGE1 immediately after preparation were 18.3 ⁇ g / ml for the acid-free formulation and 18.4 ⁇ g / ml for the acetic acid-containing formulation.
  • example designation X03 130007 the formulation of the commercial product Pridax® 20 ⁇ g / ml concentrate for solution for infusion (sample designation X03 130007) was compared with test formulations containing in each case 20 ⁇ g / ml acetic acid (sample designation X03 130007-2), malic acid (sample designation X03 130007-5), tartaric acid (Designation X03 130007-8), citric acid (designation X03 130007-1 1), acetylcysteine (designation X03 130007-14), phosphoric acid (designation X03 140006-6) and hydrochloric acid (designation X03 140006-3) and tested otherwise in the same composition ,
  • the absolute values of PGE1 immediately after preparation were between 20.0 and 20.3 ⁇ g / ml.
  • Citric acid PGA1 0.09% 0.50%
  • the accompanying graph 2 shows for the five formulations where a stabilizing effect was observed, and for the acid-free formulation, the levels of PGE1 (active ingredient) and PGA1 (degradation product) after storage for 6 weeks at 25 ° C / 65% RH. Not shown are the values of the formulations with hydrochloric acid and phosphoric acid, since no stabilization was observed here.
  • the addition of 20 ⁇ g / ml hydrochloric acid leads to a total degradation of alprostadil and its degradation product PGA1, the addition of 20 ⁇ g / ml phosphoric acid to a deterioration in stability compared to the acid-free formulation.
  • the optimum concentration for stabilization was exceeded at 20 ⁇ g / ml.
  • the optimal concentration starts slightly higher, starting at about 50 ⁇ g / ml.
  • the experiment shows that the stabilizing effect of the acid addition depends in its extent on the type of acid used.
  • the acetic acid used first has a lower stabilizing effect than polyvalent organic acids and acetylcysteine.
  • Evidence of a stabilizing effect of the strong acids phosphoric acid and hydrochloric acid is not just a nonspecific optimization of the acid concentration, analogous to the pH optimization in an aqueous system, but that, surprisingly, an acid-specific stabilization mechanism can be observed.
  • hydrochloric acid was additionally tested in the concentration range from 0.05 ⁇ g / ml to 2 ⁇ g / ml. Even with hydrochloric acid, a stabilizing effect was observed in a concentration range of 0.1 - 0.8 ug / ml, the optimum of stabilization was observed at about 0.5 ug / ml, even with an addition of 2 ug / ml was the stability significantly worse than without added acid. Detection amount or concentration of malic acid:
  • Suitable for the stabilization of alprostadil in alcoholic solution are those acids whose pKsI value is lower than the pKa value of alprostadil itself, ie lower than 4.85, and which, apart from their acidity, have no further stability-influencing properties.

Abstract

L'invention concerne une composition pharmaceutique liquide, en particulier sous forme de concentré pour la préparation d'une solution pour perfusion, ayant pour principe actif l'alprostadil, dissous dans un solvant non aqueux, et contenant au moins un acide ou une substance jouant le rôle d'acide ou de donneur de proton et faisant fonction d'agent stabilisant pour le principe actif.
EP15709819.5A 2014-01-30 2015-01-29 Solution alcoholique stable d'alprostadil Active EP3099330B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18150928.2A EP3395367A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique stable d'alprostadil

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA50063/2014A AT515356B1 (de) 2014-01-30 2014-01-30 Stabile alkoholische Lösung von Alprostadil
PCT/AT2015/050029 WO2015113094A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique d'alprostadil stable

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP18150928.2A Division-Into EP3395367A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique stable d'alprostadil
EP18150928.2A Division EP3395367A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique stable d'alprostadil

Publications (2)

Publication Number Publication Date
EP3099330A1 true EP3099330A1 (fr) 2016-12-07
EP3099330B1 EP3099330B1 (fr) 2018-03-14

Family

ID=53432896

Family Applications (2)

Application Number Title Priority Date Filing Date
EP18150928.2A Withdrawn EP3395367A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique stable d'alprostadil
EP15709819.5A Active EP3099330B1 (fr) 2014-01-30 2015-01-29 Solution alcoholique stable d'alprostadil

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP18150928.2A Withdrawn EP3395367A1 (fr) 2014-01-30 2015-01-29 Solution alcoolique stable d'alprostadil

Country Status (7)

Country Link
EP (2) EP3395367A1 (fr)
JP (1) JP2017507172A (fr)
AT (1) AT515356B1 (fr)
BR (1) BR112016016469B1 (fr)
MX (1) MX369244B (fr)
RU (1) RU2016135034A (fr)
WO (1) WO2015113094A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2695068C1 (ru) * 2018-06-26 2019-07-19 Общество с ограниченной ответственностью "Гурус БиоФарм" Средство для лечения хронических облитерирующих заболеваний периферических сосудов на основе простагландина
EE05864B1 (et) * 2021-12-22 2024-02-15 Aktsiaselts Kevelt 3-hüdroksütsüklopentoonitsüklit sisaldava ühendi kompositsioon ja meetod selle stabiliseerimiseks

Family Cites Families (11)

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Publication number Priority date Publication date Assignee Title
US3927197A (en) * 1974-04-19 1975-12-16 Pfizer Tertiary alcohol stabilized E-series prostaglandins
JPS6019734B2 (ja) * 1977-05-12 1985-05-17 三共株式会社 安定なプロスタグランジンｅ類製剤の製法
ZA831186B (en) * 1982-03-22 1983-11-30 Upjohn Ltd Gelled pge2/triacetin solutions
JPH0737389B2 (ja) * 1989-08-29 1995-04-26 久光製薬株式会社 プロスタグランジンｅ１含有の軟膏剤
KR100453803B1 (ko) 1999-07-29 2004-10-20 환인제약 주식회사 알프로스타딜 함유 외용제 조성물
UA78432C2 (uk) * 2005-08-09 2007-03-15 Закрите Акціонерне Товариство Науково-Виробничий Центр "Борщагівський Хіміко-Фармацевтичний Завод" Засіб для лікування ішемічних та гнійно-некротичних уражень нижніх кінцівок при діабетичних ангіопатіях, який містить алпростадил
WO2009093650A1 (fr) * 2008-01-24 2009-07-30 Techno Guard Co. Ltd. Emulsion grasse contenant des prostaglandines et procédé de production associé
EP2692360A4 (fr) * 2011-03-31 2014-10-29 Fujifilm Corp Émulsion grasse contenant une prostaglandine
CN102351767B (zh) * 2011-09-20 2013-03-06 海南美兰史克制药有限公司 一种前列地尔化合物及其制法
CN102688203A (zh) 2012-06-06 2012-09-26 杭州澳亚生物技术有限公司 一种前列地尔冻干粉针剂及其制备方法
CN103110579B (zh) * 2013-02-20 2014-12-10 北京德立福瑞医药科技有限公司 前列地尔注射剂

Also Published As

Publication number Publication date
JP2017507172A (ja) 2017-03-16
MX2016009458A (es) 2017-04-25
EP3099330B1 (fr) 2018-03-14
EP3395367A1 (fr) 2018-10-31
RU2016135034A (ru) 2018-03-01
BR112016016469A8 (pt) 2018-01-30
AT515356B1 (de) 2015-11-15
WO2015113094A1 (fr) 2015-08-06
AT515356A1 (de) 2015-08-15
BR112016016469A2 (pt) 2017-08-08
RU2016135034A3 (fr) 2018-05-11
MX369244B (es) 2019-11-01
BR112016016469B1 (pt) 2021-09-28

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